Substituted bicyclic methyl amine derivatives as sphingosine-1 phosphate receptors modulators

ABSTRACT

The present invention relates to novel substituted bicyclic methyl amine derivatives which are useful as sphingosine-1-phosphate receptors modulators and useful for treating a wide variety of disorders associated with modulation of sphingosine-1-phosphate receptors.

RELATED APPLICATION

This application is a divisional application of United StatesNon-Provisional patent application Ser. No. 13/445,991, filed Apr. 13,2012, which claims the benefit of U.S. Provisional Patent ApplicationSer. No. 61/476,367 filed Apr. 18, 2011, all of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel substituted bicyclic methyl aminederivatives, processes for preparing them, pharmaceutical compositionscontaining them and their use as pharmaceuticals as modulators ofsphingosine-1-phosphate receptors. The invention relates specifically tothe use of these compounds and their pharmaceutical compositions totreat disorders associated with sphingosine-1-phosphate (S1P) receptormodulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

We have now discovered a group of novel compounds which are potent andselective sphingosine-1-phosphate modulators. As such, the compoundsdescribed herein are useful in treating a wide variety of disordersassociated with modulation of sphingosine-1-phosphate receptors. Theterm “modulator” as used herein, includes but is not limited to:receptor agonist, antagonist, inverse agonist, inverse antagonist,partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:

represents a single bond

or a double bond

represents a single bond

or a double bond

or a triple bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl, or H;R² is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R³ is H, halogen, substituted or unsubstituted C₁₋₃ alkyl, C(O)R⁸ orhydroxyl;R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂, C₁₋₆ alkyl, —S(O)₂H, —P(O)MeOH,—P(O)(H)OH or OR¹¹;R⁵ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁶ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁷ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁸ is H, OR¹¹ or substituted or unsubstituted C₁₋₃ alkyl;R⁹ is H or substituted or unsubstituted C₁₋₃ alkyl;R¹⁰ is H or substituted or unsubstituted C₁₋₃ alkyl;R¹¹ is H or substituted or unsubstituted C₁₋₃ alkyl;

L¹ is O, S, NH or CH₂; L² is O, S, NH or CH₂;

a is 0 or 1;b is 0, 1, 2 or 3;c is 1, 2, 3 or 4;d is 1, 2 or 3; with the provisoswhen a is 1 then

represents

andwhen a is 0 then R¹ is O, S, NH, or CH₂.In another embodiment, the invention provides a compound having FormulaI wherein:

represents a single bond

or a double bond

represents a single bond

or a double bond

or a triple bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl, or H;R² is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R³ is H, halogen, substituted or unsubstituted C₁₋₃ alkyl, C(O)R⁸ orhydroxyl;R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂, C₁₋₆ alkyl, —S(O)₂H, —P(O)MeOH,—P(O)(H)OH or OR¹¹;R⁵ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁶ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁷ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl,CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl;R⁸ is H, OR¹¹ or substituted or unsubstituted C₁₋₃ alkyl;R⁹ is H or substituted or unsubstituted C₁₋₃ alkyl;R¹⁰ is H or substituted or unsubstituted C₁₋₃ alkyl;R¹¹ is H or substituted or unsubstituted C₁₋₃ alkyl;

L¹ is O, S, NH or CH₂; L² is O, S, NH or CH₂;

a is 1;b is 0, 1, 2 or 3;c is 1, 2, 3 or 4;d is 1, 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a double bond

represents a single bond

or a triple bond

A is substituted or unsubstituted C₆₋₁₀ aryl or H;R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is H; R⁴ is PO₃H₂, OPO₃H₂ or OR¹¹; R⁵ is H; R⁶ is H; R⁷ is H;

R¹¹ is H or substituted or unsubstituted C₁₋₃ alkyl;

L¹ is CH₂; L² is CH₂;

a is 1;b is 1;c is 1, 2, 3 or 4;d is 1, 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl or H;

R² is H; R³ is H; R⁴ is OPO₃H₂, OPO₃H₂, or OR¹¹; R⁵ is H; R⁶ is H; R⁷ isH; R¹¹ is H; L¹ is CH₂; L² is CH₂;

a is 1;b is 1;c is 1, 2, 3 or 4;d is 1, 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl or H;R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is H; R⁴ is OPO₃H₂; R⁵ is H; R⁶ is H; R⁷ is H; L¹ is CH₂; L² is CH₂;

a is 1;b is 1;c is 1, 2 or 4;d is 1, 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl;R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is H; R⁴ is OPO₃H₂; R⁵ is H; R⁶ is H; R⁷ is H; L¹ is CH₂; L² is CH₂;

a is 1;b is 1;c is 1 or 2;d is 1, 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl;

R² is H; R³ is H; R⁴ is OPO₃H₂, OPO₃H₂, or OR¹¹; R⁵ is H; R⁶ is H; R⁷ isH; R¹¹ is H; L¹ is CH₂; L² is CH₂;

a is 1;b is 1;c is 2 or 3;d is 2 or 3; and

represents

In another embodiment, the invention provides a compound having FormulaI wherein:

represents a single bond

represents a triple bond

A is substituted phenyl;

R² is H; R³ is H; R⁴ is, PO₃H₂; R⁵ is H; R⁶ is H; R⁷ is H; L¹ is CH₂; L²is CH₂;

a is 1;b is 1;c is 2;d is 1; and

represents

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 10 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalentC₃₋₁₀ cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl,cycloalkyl, amino, heterocycles, carboxylic acid, phosphonic acidgroups, sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 10 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by C₁₋₃ alkyl groups or halogens.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be saturated or non-saturated. Theheterocyclic ring can be interrupted by a C═O; the S heteroatom can beoxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclicring moieties can be substituted by hydroxyl, C₁₋₃ alkyl or halogens.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen, which can be substituted by halogenatoms, —OC₁₋₃ alkyl, C₁₋₃ alkyl, nitrile, C(O)C₁₋₃ alkyl, amino orhydroxyl groups.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

The term “nitrile”, as used herein, represents a group of formula “—CN”.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—(CO)O—”.

The term “sulfonyl” as used herein, represents a group of formula —SO₂″.

The term “amino” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) are independently selected from:hydrogen, alkyl, aryl, heterocycle as defined above.

The term “carboxylic acid” as used herein, represents a group of formula“—COOH”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—SO₂(OH)”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

Compounds of the invention are:

-   (3-{[(5-decylquinolin-8-yl)methyl]amino}propyl)phosphonic acid;-   (3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl]amino}propyl)phosphonic    acid;-   [3-({[5-(7-phenylhept-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   [3-({[5-(6-phenylhex-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   [3-({[5-(7-phenylheptyl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   (3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl]amino}butyl)phosphonic    acid;-   [3-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   [3-({[5-(5-phenylpent-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   [3-({[5-(5-phenylpentyl)quinolin-8-yl]methyl}amino)propyl]phosphonic    acid;-   2-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethanol;-   2-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethyl dihydrogen    phosphate;-   {3-[({5-[6-(3-methoxyphenyl)hex-1-yn-1-yl]quinolin-8-yl}methyl)amino]propyl}phosphonic    acid;-   {3-[({5-[6-(3-methoxyphenyl)hexyl]quinolin-8-yl}methyl)amino]propyl}phosphonic    acid;-   {3-[({5-[6-(3-methoxyphenyl)hexyl]-5,6,7,8-tetrahydroquinolin-8-yl}methyl)amino]propyl}phosphonic    acid;-   {3-[({4-[(1E)dec-1-en-1-yl]-1-naphthyl}methyl)amino]propyl}phosphonic    acid;-   [3-({[4-(6-phenylhex-1-yn-1-yl)-1-naphthyl]methyl}amino)propyl]phosphonic    acid;-   2-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)ethanol;-   2-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)ethyl dihydrogen    phosphate;-   [3-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)propyl]phosphonic    acid;-   {3-[({4-[6-(3-methoxyphenyl)hex-1-yn-1-yl]-1-naphthyl}methyl)amino]propyl}phosphonic    acid;-   2-[({4-[6-(3-methoxyphenyl)hex-1-yn-1-yl]-1-naphthyl}methyl)amino]ethyl    dihydrogen phosphate;-   {3-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]propyl}phosphonic    acid;-   2-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]ethanol;-   2-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]ethyl    dihydrogen phosphate.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic, for example, a hydrohalic suchas hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like; or an organic acid such as for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like(Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahal& Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation: not limited to the treatment of diabetic retinopathy,other retinal degenerative conditions, dry eye, angiogenesis and wounds.

Therapeutic utilities of S1P modulators are ocular diseases, such as butnot limited to: wet and dry age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity, retinal edema, geographicatrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensiveretinopathy, ocular ischemic syndrome, prevention ofinflammation-induced fibrosis in the back of the eye, various ocularinflammatory diseases including uveitis, scleritis, keratitis, andretinal vasculitis; or systemic vascular barrier related diseases suchas but not limited to: various inflammatory diseases, including acutelung injury, its prevention, sepsis, tumor metastasis, atherosclerosis,pulmonary edemas, and ventilation-induced lung injury; or autoimmunediseases and immunosuppression such as but not limited to: rheumatoidarthritis, Crohn's disease, Graves' disease, inflammatory bowel disease,multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis,antoimmune uveitis, renal ischemia/perfusion injury, contacthypersensitivity, atopic dermititis, and organ transplantation; orallergies and other inflammatory diseases such as but not limited to:urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection such as but not limited to: ischemia reperfusioninjury and atherosclerosis; or wound healing such as but not limited to:scar-free healing of wounds from cosmetic skin surgery, ocular surgery,GI surgery, general surgery, oral injuries, various mechanical, heat andburn injuries, prevention and treatment of photoaging and skin ageing,and prevention of radiation-induced injuries; or bone formation such asbut not limited to: treatment of osteoporosis and various bone fracturesincluding hip and ankles; or anti-nociceptive activity such as but notlimited to: visceral pain, pain associated with diabetic neuropathy,rheumatoid arthritis, chronic knee and joint pain, tendonitis,osteoarthritis, neuropathic pains; or central nervous system neuronalactivity in Alzheimer's disease, age-related neuronal injuries; or inorgan transplant such as renal, corneal, cardiac or adipose tissuetransplant.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular disease, wet and dry age-relatedmacular degeneration, diabetic retinopathy, retinopathy of prematurity,retinal edema, geographic atrophy, glaucomatous optic neuropathy,chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome,prevention of inflammation-induced fibrosis in the back of the eye,various ocular inflammatory diseases including uveitis, scleritis,keratitis, and retinal vasculitis; or systemic vascular barrier relateddiseases, various inflammatory diseases, including acute lung injury,its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonaryedemas, and ventilation-induced lung injury; or autoimmune diseases andimmunosuppression, rheumatoid arthritis, Crohn's disease, Graves'disease, inflammatory bowel disease, multiple sclerosis, Myastheniagravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renalischemia/perfusion injury, contact hypersensitivity, atopic dermititis,and organ transplantation; or allergies and other inflammatory diseases,urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection, ischemia reperfusion injury and atherosclerosis; orwound healing, scar-free healing of wounds from cosmetic skin surgery,ocular surgery, GI surgery, general surgery, oral injuries, variousmechanical, heat and burn injuries, prevention and treatment ofphotoaging and skin ageing, and prevention of radiation-inducedinjuries; or bone formation, treatment of osteoporosis and various bonefractures including hip and ankles; or anti-nociceptive activity,visceral pain, pain associated with diabetic neuropathy, rheumatoidarthritis, chronic knee and joint pain, tendonitis, osteoarthritis,neuropathic pains; or central nervous system neuronal activity inAlzheimer's disease, age-related neuronal injuries; or in organtransplant such as renal, corneal, cardiac or adipose tissue transplant.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier therefor. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a micelle, aliposome, and the like, wherein the resulting composition contains oneor more compounds of the present invention, as an active ingredient, inadmixture with an organic or inorganic carrier or excipient suitable forenteral or parenteral applications. Invention compounds may be combined,for example, with the usual non-toxic, pharmaceutically acceptablecarriers for tablets, pellets, capsules, suppositories, solutions,emulsions, suspensions, and any other form suitable for use. Thecarriers which can be used include glucose, lactose, gum acacia,gelatin, mannitol, starch paste, magnesium trisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea, medium chainlength triglycerides, dextrans, and other carriers suitable for use inmanufacturing preparations, in solid, semisolid, or liquid form. Inaddition auxiliary, stabilizing, thickening and coloring agents andperfumes may be used. Invention compounds are included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or disease condition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I.

The compounds of Formula I according to the invention can be preparedanalogously to conventional methods as understood by the person skilledin the art of synthetic organic chemistry. The synthetic scheme setforth below, illustrates how compounds according to the invention can bemade. Those skilled in the art will be able to routinely modify and/oradapt the following scheme to synthesize any compounds of the inventioncovered by Formula I.

A solution of 5-bromo-8-quinolinecarboxaldehyde reacts with the desiredalkyne in the presence of triethylamine and1,3-bis(diphenylphosphino)propane in DMF (10 mL) at 90° C. After coolingto RT, and extraction with ether the aldehyde intermediate is Purifiedby MPLC. The solution of aldehyde intermediate reacts with an aminoalkylphosphonic acid and tetrabutylammonium hydroxide at 50° C. and withsodium cyanoborohydride. The final compound is purified by MPLC. Thetriple bond on the aldehyde intermediate can be saturated to thecorresponding alkane in the presence of 10% palladium on carbon in ethylacetate and a H₂ balloon with stirring at RT for 16 h.

Trituration or column chromatography (methanol/ethyl acetate) gave thecorresponding compound of Formula I.

-   dppp 1,3-Bis(diphenylphosphino)propane-   Et₃N triethylamine-   DMF N,N-dimethylformamide-   NaCNBH₃ sodium cyanoborohydride-   Bu₄NOH tetrabutylammonium hydroxide    To a solution of an appropriate terminal alkyne and a desired    bromoquinolone aldehyde or bromonaphthyl aldehyde in DMF were added    triethylamine and dppp. After heating to 90° C. with stirring for 2    h, the reaction mixture was cooled to room temperature, extracted    with ether and washed with water and brine. The resulting coupled    product may be either further reduced to the alkane aryl aldhyde or    the alkyl substituted tetrahydroquinoline aldehyde. The compound of    Formula I is obtained from reductive amination between the aryl    aldehyde and the amine derivative.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows that Compound 5 lowered lymphocyte count after 24 hours ina lymphopenia assay in mice, by measuring the in vivo blood lymphocytedepletion after dosing.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

The IUPAC names of the compounds mentioned in the examples weregenerated with ACD version 8.

Unless specified otherwise in the examples, characterization of thecompounds is performed according to the following methods:

NMR spectra are recorded on 300 or 600 MHz Varian and acquired at roomtemperature. Chemical shifts are given in ppm referenced either tointernal trimethylsilyl or to the residual solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Ryan Scientific, Syn Chem, Chem-Impex, Aces Pharma,however some known intermediates, for which the CAS registry number [CAS#] are mentioned, were prepared in-house following known procedures.

Usually the compounds of the invention were purified by flash columnchromatography using a gradient solvent system ofmethanol/dichloromethane unless otherwise reported.

The following abbreviations are used in the examples:

-   -   DMF N,N-dimethylformamide    -   NaOH sodium hydroxide    -   CD₃OD deuterated methanol    -   HCl hydrochloric acid    -   CDCl₃ deuterated chloroform    -   DMSO-d₆ deuterated dimethyl sulfoxide    -   MPLC medium pressure liquid chromatography    -   THF tetrahydrofuran    -   RT room temperature    -   H₂ hydrogen    -   MeOH methanol    -   SiO₂ silicagel

Those skilled in the art will be able to routinely modify and/or adaptthe following schemes to synthesize any compound of the inventioncovered by Formula I.

Some compounds of this invention can generally be prepared in one stepfrom commercially available literature starting materials.

Example 1 Intermediate 1 1-(5-dec-1-yn-1-ylquinolin-8-yl)ethanone

A solution of 5-bromo-8-quinolinecarboxaldehyde (987 mL, 418 mmol),1-decyne (1.05 mL, 5.85 mmol), triethylamine (2 mL) and1,3-bis(diphenylphosphino)propane (dppp), (59 mg) in DMF (10 mL) washeated to 90° C. with stirring for 2 h. After cooling to RT, thereaction mixture was extracted with ether and washed with water andbrine, dried over magnesium sulfate and concentrated. Purification byMPLC (35% ethyl acetate in hexanes) gave rise to 1.04 g of Intermediate1 as yellow solid.

¹H NMR (600 MHz, CDCl₃) δ ppm 11.42 (d, J=0.88 Hz, 1H), 9.09 (dd,J=4.25, 1.61 Hz, 1H), 8.74 (dd, J=8.51, 1.47 Hz, 1H), 8.28 (d, J=7.34Hz, 1H), 7.78 (d, J=7.63 Hz, 1H), 7.59 (dd, J=8.51, 4.11 Hz, 1H), 2.60(t, J=7.19 Hz, 2H), 01.72 (m, J=14.89, 7.37, 7.37 Hz, 2H), 1.44-1.63 (m,2H), 1.19-1.44 (m, 8H), 0.89 (t, J=7.00 Hz, 3H).

Intermediates 2-6 were prepared from the corresponding aldehydes in asimilar manner to the method described in Example 1 for Intermediate 1.The reactants used and the results are described below in Table 1.

TABLE 1 Interm. Starting ¹H NMR δ (ppm) for No. IUPAC name materialCompound 2

6-heptyn-1- yl-benzene [CAS56293- 02-8] ¹H NMR (600 MHz, CDCl₃) δ 11.42(s, 1H), 9.06 (dd, J = 1.91, 3.96 Hz, 1H), 8.67 (dd, J = 1.76, 8.51 Hz,1H), 8.25 (dd, J = 1.17, 7.63 Hz, 1H), 7.73 (d, J = 7.34 Hz, 1H), 7.55(td, J = 1.91, 4.04 Hz, 1H), 7.11-7.28 (m, 5H), 2.67 (t, J = 7.78 Hz,2H), 2.60 (t, J = 7.04 Hz, 2H), 1.67-1.82 (m, 4H), 1.53-1.63 (m, 2H) 3

1-(-5-hexyn- 1-yl)-3- methoxy- benzene [CAS4383- 75-9] ¹H NMR (600 MHz,CDCl₃) δ 11.41 (s, 1H), 9.04-9.06 (m, 1H), 8.66-8.68 (m, 1H), 8.25 (dd,J = 2.35, 7.34 Hz, 1H), 7.75 (d, J = 7.63 Hz, 1H), 7.53-7.56 (m, 1H),7.22 (t, J = 7.78 Hz, 1H), 6.81 (d, J = 7.92 Hz, 1H), 6.74-6.77 (m, 2H),3.79 (s, 3H), 2.69 (t, J = 7.63 Hz, 2H), 2.63 (t, J = 7.04 Hz, 2H),1.85-1.91 (m, 2H), 1.76 (tdd, J = 7.04, 7.34, 7.48 Hz, 2H) 4

5-hexyn-1-yl- benzene [CAS100848- 88-2] ¹H NMR (600 MHz, CDCl₃) δ 11.41(d, J = 0.59 Hz, 1H), 9.05 (dd, J = 1.76, 4.11 Hz, 1H), 8.67 (dd, J =1.76, 8.51 Hz, 1H), 8.25 (d, J = 7.63 Hz, 1H), 7.75 (d, J = 7.34 Hz,1H), 7.54 (dd, J = 4.26, 8.36 Hz, 1H), 7.28- 7.31 (m, 2H), 7.19-7.23 (m,3H), 2.72 (t, J = 7.63 Hz, 2H), 2.63 (t, J = 7.04 Hz, 2H), 1.85-1.91 (m,2H), 1.74-1.79 (m, 2H) 5

1-(-5-hexyn- 1-yl)-3- methoxy- benzene [CAS4383- 75-9] ¹H NMR (600 MHz,CDCl₃) δ 10.38 (s, 1H), 9.26 (d, J = 8.51 Hz, 1H), 8.42 (d, J = 7.63 Hz,1H), 7.91 (d, J = 7.34 Hz, 1H), 7.74 (d, J = 7.34 Hz, 1H), 7.70 (ddd, J= 1.32, 6.97, 8.44 Hz, 1H), 7.64 (ddd, J = 1.17, 6.97, 8.29 Hz, 1H),7.21 (t, J = 7.92 Hz, 1H), 6.82 (d, J = 7.92 Hz, 1H), 6.74-6.78 (m, 2H),3.79 (s, 3H), 2.70 (t, J = 7.63 Hz, 2H), 2.64 (t, J = 7.04 Hz, 2H), 1.89(qd, J = 7.48, 7.68 Hz, 2H), 1.78 (dt, J = 7.30, 15.26 Hz, 2H) 6

5-hexyn-1-yl- benzene [CAS100848- 88-2] ¹H NMR (600 MHz, CDCl₃) δ 10.35(s, 1H), 9.25 (d, J = 8.51 Hz, 1H), 8.42 (d, J = 8.22 Hz, 1H), 7.88 (d,J = 7.34 Hz, 1H), 7.72 (d, J = 7.34 Hz, 1H), 7.68-7.71 (m, 1H),7.61-7.64 (m, 1H), 7.27-7.31 (m, 2H), 7.17-7.24 (m, 3H), 2.72 (t, J =7.63 Hz, 2H), 2.63 (t, J = 7.04 Hz, 2H), 1.86-1.92 (m, 2H), 1.77 (tdd, J= 7.04, 7.34, 7.48 Hz, 2H) 7

4- pentynyl- benzene [CAS1823- 14-9] ¹H NMR (600 MHz, CDCl₃) δ 11.39 (d,J = 0.59 Hz, 1H), 8.99 (dd, J = 1.76, 4.11 Hz, 1H), 8.62 (dd, J = 2.64,9.10 Hz, 1H), 8.20 (d, J = 7.04 Hz, 1H), 7.70 (d, J = 7.63 Hz, 1H), 7.49(dd, J = 4.11, 8.51 Hz, 1H), 7.28- 7.32 (m, 2H), 7.19-7.25 (m, 3H), 2.84(t, J = 7.63 Hz, 2H), 2.59 (t, J = 7.04 Hz, 2H), 2.04 (qd, J = 7.19,7.39 Hz, 2H)

Example 2 Intermediate 8 5-decylquinoline-8-carbaldehyde

A reaction mixture of Intermediate 1 (368 mg, 1.25 mmol) and 10%palladium on carbon in 30 mL ethyl acetate was submitted to H₂ balloonatmosphere with stirring at RT for 16 h. Filtration through a shortcolumn of SiO₂, concentration in vacuum, and purification by MPLCafforded 204 mg of Intermediate 8.

¹H NMR (300 MHz, CDCl₃) δ 11.42 (d, J=0.88 Hz, 1H), 9.04 (dd, J=1.76,4.10 Hz, 1H), 8.44 (dd, J=1.76, 8.79 Hz, 1H), 8.26 (d, J=7.33 Hz, 1H),7.53 (d, J=4.10 Hz, 1H), 7.40-7.68 (m, 1H), 3.11 (dd, J=7.90, 7.90 Hz,2H), 1.62-1.90 (m, 2H), 1.13-1.55 (m, 14H), 0.88 (t, J=6.74 Hz, 3H).

Intermediates 9-15 were prepared from the corresponding aldehydes in asimilar manner to the method described in Example 2 for Intermediate 3.The reactants used and the results are described below in Table 2.

TABLE 2 Interm. Starting ¹H NMR δ (ppm) for No. IUPAC name materialCompound 9

Intermediate 2 ¹H NMR (300 MHz, CDCl₃) δ 11.42 (s, 1H), 9.03 (dd, J =1.61, 4.25 Hz, 1H), 8.42 (dd, J = 1.76, 8.50 Hz, 1H), 8.25 (d, J = 7.33Hz, 1H), 7.51 (t, J = 4.25 Hz, 1H), 7.49 (d, J = 1.17 Hz, 1H), 7.08-7.34(m, 5H), 3.09 (dd, J = 7.90 Hz, 2H), 2.48- 2.68 (m, 4H), 1.13-1.88 (m,8H). 10

Intermediate 4 ¹H NMR (600 MHz, CDCl₃) δ 11.43 (s, 1H), 8.97-9.04 (m,1H), 8.37 (dd, J = 1.61, 8.66 Hz, 1H), 8.22 (d, J = 7.34 Hz, 1H),7.41-7.51 (m, 2H), 7.24-7.30 (m, 2H), 7.13-7.21 (m, 3H), 3.05 (t, J =7.48 Hz, 2H), 2.60 (t, J = 7.78 Hz, 2H), 1.71 (quin, J = 7.56 Hz, 2H),1.63 (dt, J = 7.59, 15.04 Hz, 2H), 1.35- 1.50 (m, 4H) 11

Intermediate 3 ¹H NMR (300 MHz, CDCl₃) δ 11.42 (s, 1H), 9.04 (dd, J =1.76, 4.10 Hz, 1H), 8.42 (dd, J = 1.76, 8.50 Hz, 1H), 8.25 (d, J = 7.62Hz, 1H), 7.47-7.54 (m, 2H), 7.14- 7.22 (m, 2H), 6.64-6.77 (m, 2H), 3.79(s, 3H), 3.11 (d, J = 7.62 Hz, 1H), 3.02 (t, J = 7.90 Hz, 1H), 2.58 (t,J = 7.62 Hz, 2H), 1.36-1.80 (m, 8H) 12

Intermediate 3 ¹H NMR (300 MHz, CDCl₃) δ 9.69 (s, 1H), 8.51 (br. s.,1H), 7.15-7.21 (m, 2H), 6.69-6.78 (m, 3H), 6.42 (d, J = 7.91 Hz, 1H),3.78 (s, 3H), 3.39 (t, J = 4.54 Hz, 2H), 2.70 (t, J = 6.30 Hz, 2H), 2.58(t, J = 7.00 Hz, 2H), 2.50 (t, J = 7.60 Hz, 2H), 1.92 (quin, J = 6.20Hz, 2H), 1.48-1.67 (m, 4H), 1.34-1.44 (m, 4H) 13

Intermediate 5 ¹H NMR (600 MHz, CDCl₃) δ 10.33 (s, 1H), 9.33 (dd, J =0.88, 8.51 Hz, 1H), 8.11 (d, J = 8.51 Hz, 1H), 7.88 (d, J = 7.34 Hz,1H), 7.67 (ddd, J = 1.32, 6.97, 8.44 Hz, 1H), 7.60 (ddd, J = 1.32, 6.97,8.44 Hz, 1H), 7.46 (d, J = 7.34 Hz, 1H), 7.17-7.20 (m, 1H), 6.76 (d, J =7.92 Hz, 1H), 6.71-6.73 (m, 2H), 3.78 (s, 3H), 3.12 (t, J = 7.30 Hz,2H), 2.58 (t, J = 7.60 Hz, 2H), 1.77 (dt, J = 7.74, 15.33 Hz, 2H), 1.63(dt, J = 7.59, 15.04 Hz, 2H), 1.38-1.50 (m, 4H) 14

Intermediate 6 ¹H NMR (300 MHz, CDCl₃) δ 10.34 (s, 1H), 9.33 (d, J =8.51 Hz, 1H), 8.12 (d, J = 8.51 Hz, 1H), 7.90 (d, J = 7.04 Hz, 1H),7.67-7.70 (m, 1H), 7.60-7.63 (m, 1H), 7.47 (d, J = 7.34 Hz, 1H), 7.26(s, 1H), 7.27 (t, J = 7.00 Hz, 1H), 7.15-7.19 (m, 3H), 3.13 (t, J = 7.90Hz, 2H), 2.61 (t, J = 7.78 Hz, 2H), 1.78 (ddd, J = 7.70, 7.92, 15.19 Hz,2H), 1.64 (dt, J = 7.63, 15.26 Hz, 2H), 1.48 (ddd, J = 7.19, 7.41, 15.04Hz, 2H), 1.41 (ddd, J = 7.00, 7.63, 14.97 Hz, 2H) 15

Intermediate 7 ¹H NMR (600 MHz, CDCl₃) δ 511.42 (d, J = 0.88 Hz, 1H),9.03 (dd, J = 1.61, 3.96 Hz, 1H), 8.41 (dd, J = 1.61, 8.66 Hz, 1H), 8.24(d, J = 7.34 Hz, 1H), 7.51 (dd, J = 4.25, 8.66 Hz, 1H), 7.48 (d, J =7.63 Hz, 1H), 7.25-7.29 (m, 2H), 7.14-7.20 (m, 3H), 3.09 (t, J = 7.90Hz, 2H), 2.61 (t, J = 7.78 Hz, 2H), 1.76 (ddd, J = 7.78, 7.92, 15.41 Hz,2H), 1.69 (dt, J = 7.67, 15.48 Hz, 2H), 1.47 (quin, J = 7.63 Hz, 2H)

Example 3 Intermediate 16 4-[(1E)-dec-1-en-1-yl]-1-naphthaldehyde

To a solution of 1-decyne (1378 g, 12.89 mmol) in THF (40 mL) at RT wasadded catecholborane (1M in THF, 21 mL, 21 mmol) with stirring. Afterheating to reflux for 3.5 h, the reaction mixture was cooled to RT,4-bromonaphthalene-1-carboxaldehyde (CAS 50672-84-9) (2.0 g, 8.51 mmol)and tetrakis(triphenylphosphine)palladium(0) (893 mg, 0.77 mmol) wereadded. After the reaction mixture was stirred for 20 min at RT, Na₂CO₃(2M solution, 12.9 mL) was added and heated to reflux for 16 h withstirring. The mixture was cooled to RT, quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, and dried over magnesium sulfate. The resultingproduct was purified by MPLC (hexanes) to afford 353 mg of Intermediate16 as yellow solid.

¹H NMR (600 MHz, CDCl₃) δ 10.31 (s, 1H), 9.29 (dd, J=0.59, 8.51 Hz, 1H),8.17 (d, J=8.22 Hz, 1H), 7.86 (d, J=7.34 Hz, 1H), 7.63-7.67 (m, 2H),7.57 (ddd, J=1.32, 6.97, 8.44 Hz, 1H), 7.11 (d, J=15.55 Hz, 1H), 6.36(dt, J=7.04, 15.55 Hz, 1H), 2.34 (tdd, J=1.61, 7.04, 7.41 Hz, 2H), 1.55(dt, J=7.30, 14.97 Hz, 2H), 1.24-1.42 (m, 10H), 0.89 (t, J=7.30 Hz, 3H)

Example 4 Intermediate 17 1-(5-dec-1-yn-1-ylquinolin-8-yl)ethanone

To a solution of Intermediate 1 (470 mg, 1.6 mmol) in THF (10 mL) at−78° C. was added methyl lithium (1.6 M in ether) dropwise withstirring. After 45 min, a solution of N-t-butyl benzenesulfinimidoylchloride (518 mg, 2.4 mmol) in THF (3 mL) was added dropwise withstirring at −78° C. for 20 min. The reaction mixture was warmed to RTover 20 min then quenched with HCl (2M, 10 mL) and extracted with ethylacetate. The organic layers were washed with 2M HCl and extracted withethyl acetate, dried with magnesium sulfate, concentrated in vacuum andpurified by MPLC (20% ethyl acetate in hexanes) to afford 123 mg ofIntermediate 17.

¹H NMR (600 MHz, CDCl₃) δ 8.98 (dd, J=1.76, 3.81 Hz, 1H), 8.67 (dd,J=1.91, 8.36 Hz, 1H), 7.88 (d, J=7.63 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H),7.50 (dd, J=4.10, 8.51 Hz, 0H), 2.93 (s, 3H), 2.57 (t, J=7.19 Hz, 2H),1.71 (dt, J=7.37, 14.89 Hz, 2H), 1.52 (ddd, J=7.19, 7.41, 15.04 Hz, 2H),1.25-1.41 (m, 8H), 0.89 (t, J=6.90 Hz, 3H).

Example 5 Compound 1(3-{[(5-decylquinolin-8-yl)methyl]amino}propyl)phosphonic acid

To a solution of Intermediate 8 (193 mg, 0.65 mmol) in MeOH (15 mL) wasadded (3-aminopropyl) phosphonic acid (90 mg) and tetrabutylammoniumhydroxide (1M in MeOH). The reaction mixture was heated to 50° C. for 30min with stirring, then sodium cyanoborohydride (41 mg, 0.65 mmol) wasadded. The reaction mixture was heated to 50° C. with stirring for 3 h.After cooling to RT, the mixture was dried over magnesium sulfate,concentrated and purified by MPLC (0-100% ethyl acetate in hexanes) togive 120 mg of Compound 1.

¹H NMR (600 MHz, CD₃OD) δ 8.98 (dd, J=1.61, 4.26 Hz, 1H), 8.60 (dd,J=1.61, 8.66 Hz, 1H), 7.79 (d, J=7.34 Hz, 1H), 7.63 (dd, J=4.25, 8.66Hz, 1H), 7.48 (d, J=7.34 Hz, 1H), 4.69 (s, 2H), 3.17 (t, J=6.60 Hz, 2H),3.12 (dd, J=7.90 Hz, 2H), 1.92-2.10 (m, J=7.01, 7.01, 17.09 Hz, 2H),1.62-1.85 (m, 4H), 1.22-1.50 (m, 14H), 0.89 (t, J=7.30 Hz, 3H).

Compounds 2-24 were prepared from the corresponding aldehydes in asimilar manner to the method described in Example 5 for Compound 1. Thereactants used and the results are described below in Table 3.

TABLE 3 Comp Starting ¹H NMR δ (ppm) for No. IUPAC name materialCompound 2

Interm. 1 ¹H NMR (300 MHz, CD₃OD) δ 9.01 (dd, J = 1.61, 4.25 Hz, 1H),8.72 (dd, J = 1.76, 8.50 Hz, 1H), 7.83 (d, J = 7.33 Hz, 1H), 7.67 (dd, J= 4.10, 9.10 Hz, 1H), 7.69 (d, J = 7.62 Hz, 1H), 4.72 (s, 2H), 3.19 (t,J = 6.74 Hz, 2H), 2.60 (t, J = 6.89 Hz, 2H), 1.91-2.18 (m, 2H),1.61-1.81 (m, 4H), 1.48- 1.61 (m, 2H), 1.23-1.48 (m, 8H), 0.89 (t, J =7.00 Hz, 3H). 3

Interm. 2 ¹H NMR (600 MHz, CD₃OD) δ 8.97 (dd, J = 1.61, 4.26 Hz, 1H),8.61 (dd, J = 1.76, 8.51 Hz, 1H), 7.81 (d, J = 7.63 Hz, 1H), 7.61 (d, J= 7.34 Hz, 1H), 7.59 (dd, J = 4.40, 8.51 Hz, 1H), 7.08-7.23 (m, 5H),4.66 (s, 1H), 3.12 (t, J = 6.75 Hz, 2H), 2.62 (t, J = 7.48 Hz, 2H), 2.55(t, J = 7.04 Hz, 2H), 2.02 (dqd, J = 6.46, 6.90, 16.73 Hz, 2H),1.61-1.74 (m, 6H), 1.50-1.59 (m, 2H). 4

Interm. 4 ¹H NMR (600 MHz, CD₃OD) δ 8.99 (dd, J = 1.47, 4.11 Hz, 1H),8.66 (dd, J = 1.47, 8.51 Hz, 1H), 7.82 (d, J = 7.63 Hz, 1H), 7.66 (d, J= 7.34 Hz, 1H), 7.62 (ddd, J = 1.47, 4.26, 8.36 Hz, 1H), 7.25 (s, 2H),7.20 (d, J = 7.04 Hz, 2H), 7.15 (t, J = 7.63 Hz, 1H), 4.68 (s, 2H),3.11-3.18 (m, 1H), 2.70 (t, J = 7.63 Hz, 2H), 2.61 (t, J = 7.04 Hz, 2H),2.01 (dquin, J = 6.75, 17.00 Hz, 2H), 1.86 (dt, J = 7.63, 15.26 Hz, 2H),1.62-1.76 (m, 4H) 5

Interm. 9 ¹H NMR (600 MHz, CD₃OD) δ 8.96 (dd, J = 1.61, 4.26 Hz, 1H),8.55 (dd, J = 1.47, 8.51 Hz, 1H), 7.78 (d, J = 7.34 Hz, 1H), 7.59 (dd, J= 4.11, 8.51 Hz, 1H), 7.44 (d, J = 7.34 Hz, 1H), 7.17-7.31 (m, 2H),7.09- 7.18 (m, 3H), 4.66 (s, 2H), 3.13 (t, J = 6.60 Hz, 2H), 3.08 (dd, J= 7.90, 8.51 Hz, 2H), 2.56 (t, J = 7.63 Hz, 2H), 2.01 (dquin, J = 6.75,17.02 Hz, 2H), 1.62-1.79 (m, 4H), 1.58 (dt, J = 7.59, 15.04 Hz, 2H),1.25-1.48 (m, 6H) 6

Interm. 17 ¹H NMR (600 MHz, CD₃OD) δ 8.98 (dd, J = 1.76, 4.40 Hz, 1H),8.75 (dd, J = 1.76, 8.22 Hz, 1H), 7.77 (d, J = 7.63 Hz, 1H), 7.70 (d, J= 7.34 Hz, 1H), 7.67 (dd, J = 4.25, 8.36 Hz, 1H), 5.04 (q, J = 6.70 Hz,1H), 2.92 (ddd, J = 5.14, 7.41, 12.69 Hz, 1H), 2.80 (ddd, J = 5.30,7.04, 12.00 Hz, 1H), 2.60 (t, J = 7.04 Hz, 2H), 1.92 (d, J = 6.75 Hz,2H), 1.80 (d, J = 6.75 Hz, 3H), 1.71 (ddd, J = 7.19, 7.34, 14.82 Hz,2H), 1.59-1.67 (m, J = 9.10, 15.00 Hz, 2H), 1.52-1.59 (m, 2H), 1.28-1.44(m, 8H), 0.89 (t, J = 7.04 Hz, 3H) 7

Interm. 10 ¹H NMR (600 MHz, CD₃OD) δ 8.97 (dd, J = 1.47, 4.11 Hz, 1H),8.57 (dd, J = 1.76, 8.51 Hz, 1H), 7.78 (d, J = 7.34 Hz, 1H),7.61 (dd, J= 4.11, 8.51 Hz, 1H), 7.46 (d, J = 7.34 Hz, 1H), 7.16-7.26 (m, 1H), 7.13(d, J = 7.63 Hz, 3H), 4.68 (s, 2H), 3.15 (t, J = 6.60 Hz, 2H), 3.10 (s,2H), 2.58 (t, J = 7.63 Hz, 2H), 2.01 (dqd, J = 6.60, 6.87, 17.39 Hz,2H), 1.56- 1.76(m, 6H), 1.35-1.50 (m, 4H) 8

Interm. 7 ¹H NMR (600 MHz, CD₃OD) δ: 8.99 (dd, J = 4.0, 1.6 Hz, 1H),8.68 (dd, J = 8.1, 1.6 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.68 (d, J =7.3 Hz, 1H), 7.64 (dd, J = 8.4, 4.3 Hz, 1H), 7.22- 7.29 (m, 4H), 7.17(t, J = 7.3 Hz, 1H), 4.69 (s, 2H), 3.15 (t, J = 6.7 Hz, 2H), 2.83 (t, J= 7.5 Hz, 2H), 2.57 (t, J = 7.0 Hz, 2H), 1.96-2.07 (m, 4H), 1.63-1.71(m, 2H) 9

Interm. 15 ¹H NMR (600 MHz, CD₃OD) δ: 8.96 (dd, J = 4.1, 1.5 Hz, 1H),8.53 (dd, J = 8.7, 1.6 Hz, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.59 (dd, J =8.5, 4.1 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.20- 7.23 (m, 2H),7.10-7.13 (m, 3H), 4.65 (s, 2H), 3.12 (t, J = 6.7 Hz, 2H), 3.06 (t, J =7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.02 (dquin, J = 17.0, 7.0 Hz,2H), 1.62-1.73 (m, 6H), 1.40-1.45 (m, 2H) 10

Interm. 10 ¹H NMR (600 MHz, CDCl₃) δ 8.89 (dd, J = 1.76, 4.11 Hz, 1H),8.23-8.48 (m, 1H), 7.56 (d, J = 7.34 Hz, 1H), 7.43 (dd, J = 4.11, 8.51Hz, 1H), 7.25- 7.31 (m, 3H), 7.15-7.19 (m, 3H), 4.32 (s, 2H), 3.75 (t, J= 5.00 Hz, 2H), 3.00-3.03 (m, J = 7.92 Hz, 2H), 2.86 (t, J = 5.30 Hz,2H), 2.60 (t, J = 7.63 Hz, 2H), 1.70 (dt, J = 7.52, 15.19 Hz, 2H), 1.63(dt, J = 7.52, 15.19 Hz, 2H), 1.36- 1.47 (m, 4H) 11

Interm. 10 ¹H NMR (600 MHz, CD₃OD) δ: 9.02-9.03 (m, 1H), 8.68- 8.71 (m,1H), 7.82 (dd, J = 7.2, 2.5 Hz, 1H), 7.70 (ddd, J = 8.7, 4.4, 1.3 Hz,1H), 7.52 (d, J = 7.3 Hz, 1H), 7.21- 7.24 (m, 2H), 7.13 (d, J = 7.6 Hz,3H), 4.80 (s, 2H), 4.29- 4.33 (m, 2H), 3.43 (t, J = 4.5 Hz, 2H), 3.14(t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.73 (dt, J = 15.0, 7.6Hz, 2H), 1.61 (dt, J = 15.0, 7.5 Hz, 2H), 1.36-1.49 (m, 4H) 12

Interm.3 ¹H NMR (600 MHz, CD₃OD) δ 9.02 (dd, J = 1.76, 4.40 Hz, 1H),8.72 (dd, J = 1.61, 8.36 Hz, 1H), 7.81 (d, J = 7.34 Hz, 1H), 7.71 (d, J= 7.63 Hz, 1H), 7.68 (dd, J = 4.11, 8.51 Hz, 1H), 7.17 (t, J = 7.78 Hz,1H), 6.77-6.80 (m, 2H), 6.73 (dd, J = 3.08, 7.78 Hz, 1H), 4.75 (s, 2H),3.75 (s, 3H), 3.24 (t, J = 7.30 Hz, 2H), 2.69 (t, J = 7.63 Hz, 2H), 2.64(t, J = 6.90 Hz, 2H), 2.08 (tdd, J = 7.63, 7.78, 14.89 Hz, 2H),1.81-1.90 (m, 4H), 1.71- 1.76 (m, 2H) 13

Interm. 11 ¹H NMR (600 MHz, CD₃OD) δ 8.97 (dd, J = 1.47, 4.11 Hz, 1H),8.58 (dd, J = 1.61, 8.66 Hz, 1H), 7.78 (d, J = 7.34 Hz, 1H), 7.62 (dd, J= 4.11, 8.51 Hz, 1H), 7.46 (d, J = 7.04 Hz, 1H), 7.12-7.15 (m, 1H),6.69- 6.72 (m, 3H), 4.69 (s, 2H), 3.75 (s, 3H), 3.16 (t, J = 6.60 Hz,2H), 3.11 (t, J = 7.63 Hz, 2H), 2.55 (t, J = 7.78 Hz, 2H), 2.01 (ddt, J= 6.86, 13.68, 17.20 Hz, 2H), 1.66-1.74 (m, 4H), 1.60 (dt, J = 7.52,15.19 Hz, 2H), 1.45 (ddd, J = 7.34, 7.48, 15.11 Hz, 2H), 1.35- 1.41 (m,2H) 14

Interm. 12 ¹H NMR (600 MHz, CD₃OD) δ 7.30 (d, J = 7.92 Hz, 1H), 7.15(dd, J = 7.63, 8.80 Hz, 1H), 7.10 (d, J = 7.63 Hz, 1H), 6.70-6.74 (m,4H), 4.23 (s, 2H), 3.76 (s, 3H), 3.48-101 3.50 (m, 2H), 3.24 (t, J =7.34 Hz, 2H), 2.85 (t, J = 6.46 Hz, 2H), 2.62 (t, J = 7.60 Hz, 2H), 2.57(t, J = 7.63 Hz, 2H), 2.01- 2.11 (m, 4H), 1.85 (dt, J = 7.34, 18.49 Hz,2H), 1.54- 1.64 (m, 4H), 1.35-1.44 (m, 4H) 15

Interm. 16 ¹H NMR (600 MHz, CD₃OD) δ 8.26 (d, J = 7.92 Hz, 1H), 8.14 (d,J = 8.22 Hz, 1H), 7.68 (ddd, J = 1.17, 6.75, 8.51 Hz, 1H), 7.61-7.64 (m,3H), 7.18 (d, J = 15.55 Hz, 1H), 6.33 (dt, J = 7.04, 15.55 Hz, 1H), 4.70(s, 2H), 3.29 (t, J = 7.60 Hz, 2H), 2.37 (tdd, J = 1.47, 7.04, 7.60 Hz,2H), 2.07 (tt, J = 7.63, 15.26 Hz, 2H), 1.85 (dt, J = 7.63, 18.49 Hz,2H), 1.58 (quin, J = 7.41 Hz, 2H), 1.30-1.47 (m, 5H), 0.90 (t, J = 7.30Hz, 3H) 16

Interm. 6 ¹H NMR (600 MHz, CD₃OD) δ 8.43 (dd, J = 0.59, 8.22 Hz, 1H),8.16 (d, J = 8.51 Hz, 1H), 7.71 (ddd, J = 1.47, 6.97, 8.29 Hz, 1H),7.64-7.67 (m, 1H), 7.63 (dd, J = 7.34, 23.48 Hz, 2H), 7.21-7.27 (m, 4H),7.14-7.17 (m, 1H), 4.71 (s, 2H), 3.30 (t, J = 7.90 Hz, 2H), 2.72 (t, J =7.63 Hz, 2H), 2.63 (t, J = 7.04 Hz, 2H), 2.07 (tt, J = 7.63, 15.26 Hz,2H), 1.82- 1.92 (m, 4H), 1.74 (ddd, J = 7.04, 7.90, 15.26 Hz, 2H) 17

Interm. 14 ¹H NMR (600 MHz, CD₃OD) δ8.02-8.11 (m, 2H), 7.46- 7.53 (m,2H), 7.34-7.39 (m, 1H), 7.18-7.25 (m, 3H), 7.08- 7.12 (m, 3H), 4.15-4.19(m, 2H), 3.68 (q, J = 5.67 Hz, 2H), 2.96-3.04 (m, 2H), 2.79- 2.84 (m,2H), 2.49-2.56 (m, 2H), 1.63-1.71 (m, 2H), 1.52- 1.60 (m, 2H), 1.29-1.44(m, 4H) 18

Interm. 14 ¹H NMR (600 MHz, CD₃OD) δ 8.16-8.21 (m, 2H), 7.60- 7.71 (m,3H), 7.41 (d, J = 7.33 Hz, 1H), 7.19-7.27 (m, 2H), 7.10-7.16 (m, 3H),4.76 (s, 2H), 4.30-4.36 (m, 2H), 3.48 (t, J = 4.84 Hz, 2H), 3.12 (t, J =7.90 Hz, 2H), 2.59 (t, J = 7.90 Hz, 2H), 1.75 (quin, J = 7.55 Hz, 2H),1.62 (dt, J = 7.44, 14.72 Hz, 2H), 1.36- 1.52 (m, 4H) 19

Interm. 14 ¹H NMR (600 MHz, CD₃OD) δ 8.14 (d, J = 8.51 Hz, 2H),7.60-7.66 (m, 2H), 7.58 (d, J = 7.34 Hz, 1H), 7.38 (d, J = 7.34 Hz, 1H),7.21-7.24 (m, 2H), 7.11-7.14 (m, 3H), 4.60 (s, 2H), 3.20 (t, J = 6.31Hz, 2H), 3.09 (t, J = 7.30 Hz, 2H), 2.59 (t, J = 7.00 Hz, 2H), 2.01(ddt, J = 6.60, 12.95, 19.33 Hz, 2H), 1.69-1.76 (m, 4H), 1.61 (dt, J =7.63, 15.26 Hz, 2H), 1.46 (dt, J = 7.30, 15.26 Hz, 2H), 1.37-1.42 (m,2H) 20

Interm. 5 ¹H NMR (600 MHz, CD₃OD) δ 8.43 (dd, J = 0.73, 8.36 Hz, 1H),8.16 (d, J = 8.51 Hz, 1H), 7.71 (ddd, J = 1.50, 7.00, 8.51 Hz, 1H),7.64-7.67 (m, 1H), 7.65 (d, J = 7.34 Hz, 1H), 7.61 (d, J = 7.34 Hz, 1H),7.17 (t, J = 7.78 Hz, 1H), 6.78-6.81 (m, 2H), 6.73 (dd, J = 2.35, 8.22Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 3.30 (t, J = 7.90 Hz, 2H), 2.69 (t,J = 7.63 Hz, 2H), 2.63 (t, J = 6.90 Hz, 2H), 2.07 (tt, J = 7.63, 15.26Hz, 2H), 1.82-1.92 (m, 4H), 1.74 (dt, J = 7.34, 15.26 Hz, 2H) 21

Interm. 5 ¹H NMR (600 MHz, CD₃OD) δ 8.43 (d, J = 8.22 Hz, 1H), 8.18 (d,J = 8.51 Hz, 1H), 7.72 (ddd, J = 1.32, 6.97, 8.44 Hz, 1H), 7.66 (d, J =7.04 Hz, 1H), 7.65-7.68 (m, 1H), 7.63 (d, J = 7.34 Hz, 1H), 7.17 (t, J =7.92 Hz, 1H), 6.78-6.81 (m, 2H), 6.73 (dd, J = 2.49, 8.07 Hz, 1H), 4.78(s, 2H), 4.31-4.34 (m, 2H), 3.74 (s, 3H), 3.49 (dd, J = 4.69, 5.28 Hz,2H), 2.69 (t, J = 7.63 Hz, 2H), 2.63 (t, J = 7.04 Hz, 2H), 1.87-1.92 (m,2H), 1.74 (tdd, J = 7.04, 7.26, 7.37 Hz, 2H) 22

Interm. 13 ¹H NMR (600 MHz, CD₃OD) δ 8.16-8.21 (m, 2H), 7.60- 7.70 (m,3H), 7.43 (d, J = 7.34 Hz, 1H), 7.16 (t, J = 7.60 Hz, 1H), 6.71-6.76 (m,3H), 4.72 (s, 2H), 3.78 (s, 3H), 3.30-3.33 (m, 2H), 3.13 (t, J = 7.30Hz, 2H), 2.58 (t, J = 7.90 Hz, 2H), 2.07-2.15 (m, 2H), 1.84-1.91 (m,2H), 1.68- 1.79 (m, 3H), 1.60-1.65 (m, 1H), 1.39-1.51 (m, 4H) 23

Interm. 13 ¹H NMR (600 MHz, CD₃OD) δ 8.09 (dd, J = 1.32, 8.07 Hz, 1H),8.05 (dd, J = 1.32, 8.07 Hz, 1H), 7.50 (tdd, J = 6.02, 7.48, 7.78 Hz,2H), 7.36 (d, J = 7.34 Hz, 1H), 7.23 (d, J = 7.34 Hz, 1H), 7.12 (dd, J =7.19, 8.95 Hz, 1H), 6.67- 6.70 (m, 3H), 4.17 (s, 2H), 3.72 (s, 3H), 3.68(t, J = 5.60 Hz, 2H), 3.00 (t, J = 7.90 Hz, 2H), 2.81 (t, J = 5.90 Hz,2H), 2.51 (t, J = 7.90 Hz, 2H), 1.67 (dt, J = 7.52, 15.19 Hz, 2H), 1.56(dt, J = 7.59, 15.04 Hz, 2H), 1.31-1.43 (m, 4H) 24

Interm. 13 ¹H NMR (600 MHz, CD₃OD) δ 8.18 (t, J = 8.95 Hz, 2H), 7.67(ddd, J = 1.17, 6.75, 8.22 Hz, 1H), 7.63 (ddd, J = 1.47, 6.75, 8.51 Hz,1H), 7.60 (d, J = 7.04 Hz, 1H), 7.41 (d, J = 7.34 Hz, 1H), 7.13-7.16 (m,1H), 6.70-6.73 (m, 3H), 4.76 (s, 2H), 4.31-4.34 (m, 2H), 3.75 (s, 3H),3.47 (t, J = 4.70 Hz, 2H), 3.12 (t, J = 7.60 Hz, 2H), 2.56 (t, J = 7.30Hz, 2H), 1.74 (dt, J = 7.63, 15.26 Hz, 2H), 1.61 (dt, J = 7.59, 15.04Hz, 2H), 1.37-1.49 (m, 4H)

Example 6 Biological Data

Novel compounds were synthesized and tested for S1P1 activity using theGTP γ³⁵S binding assay. These compounds may be assessed for theirability to activate or block activation of the human S1P1 receptor incells stably expressing the S1P1 receptor. GTP γ³⁵S binding was measuredin the medium containing (mM) HEPES 25, pH 7.4, MgCl₂ 10, NaCl 100,dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP γ³⁵S, and 5 μgmembrane protein in a volume of 150 μl. Test compounds were included inthe concentration range from 0.08 to 5,000 nM unless indicatedotherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P1 in the presence of test antagonist atconcentrations ranging from 0.08 to 5000 nM.

Activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀).

TABLE 4 S1P1 EC₅₀ IUPAC name (nM)(3-{[(5-decylquinolin-8-yl)methyl]amino}propyl) 1.53 phosphonic acid(3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl] amino}propyl) 3.39 phosphonicacid (3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl]amino}butyl) 126phosphonic acid [3-({[5-(7-phenylhept-1-yn-1-yl)quinolin-8- 94yl]methyl}amino)propyl]phosphonic acid[3-({[5-(7-phenylheptyl)quinolin-8-yl]methyl}amino)propyl] 173phosphonic acid [3-({[5-(6-phenylhex-1-yn-1-yl)quinolin-8- 204yl]methyl}amino)propyl]phosphonic acid[3-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)propyl] 5.45phosphonic acid [3-({[5-(5-phenylpent-1-yn-1-yl)quinolin-8- 543yl]methyl}amino)propyl]phosphonic acid2-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethanol 6372-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethyl 2.19 dihydrogenphosphate {3-[({4-[(1E)-dec-1-en-1-yl]-1- 138naphthyl}methyl)amino]propyl}phosphonic acid{3-[({5-[6-(3-methoxyphenyl)hexyl]quinolin-8- 7.68yl}methyl)amino]propyl}phosphonic acid{3-[({5-[6-(3-methoxyphenyl)hex-1-yn-1-yl]quinolin-8- 18.3yl}methyl)amino]propyl}phosphonic acid[3-({[4-(6-phenylhex-1-yn-1-yl)-1- 4.88naphthyl]methyl}amino)propyl]phosphonic acid[3-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)propyl] 5.59 phosphonicacid 2-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)ethyl 55.5dihydrogen phosphate

Example 7 Lymphopenia Assay in Mice

Test drugs are prepared in a solution containing 3% (w/v) 2-hydroxypropyl β-cyclodextrin (HPBCD) and 1% DMSO to a final concentration of 1mg/ml, and subcutaneously injected to female C57BL6 mice (CHARLESRIVERS) weighing 20-25 g at the dose of 10 mg/Kg. Blood samples areobtained by puncturing the submandibular skin with a Goldenrod animallancet at 5, 24, 48, 72, and 96 hrs post drug application. Blood iscollected into microvettes (SARSTEDT) containing EDTA tripotassium salt.Lymphocytes in blood samples are counted using a HEMAVET MultispeciesHematology System, HEMAVET HV950FS (Drew Scientific Inc.). (Hale, J. etal Bioorg. & Med. Chem. Lett. 14 (2004) 3351).

A lymphopenia assay in mice, as previously described, was employed tomeasure the in vivo blood lymphocyte depletion after dosing Compound 5(FIG. 1). These S1P agonists (or modulators) are useful for S1P-relateddiseases, and exemplified by the lymphopenia in vivo response. Ingeneral, test compounds were prepared in a solution containing 3% (w/v)2-hydroxy propyl β-cyclodextrin (HPBCD) and 1% DMSO to a finalconcentration of 1 mg/ml, and subcutaneously injected to female C57BL6mice (CHARLES RIVERS) weighing 20-25 g at the dose of 10 mg/Kg or 2mg/Kg. Blood samples were obtained by puncturing the submandibular skinwith a Goldenrod animal lancet at 24, 48, 72 and 96 hrs post drugapplication. Blood was collected into microvettes (SARSTEDT) containingEDTA tripotassium salt. Lymphocytes in blood samples were counted usinga HEMAVET Multispecies Hematology System, HEMAVET HV950FS (DrewScientific Inc.). Results are shown in FIG. 1 that depict loweredlymphocyte count after 24 hours (<1 number of lymphocytes 10³/μL blood).

What is claimed is:
 1. A method of treating an immunosuppressantdisorder associated with the sphingosine-1-phosphate receptormodulation, wherein the immunosuppressant disorder is selected from:rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis,dry eye, inflammatory bowel diseases, atopic allergy, atopic dermatitis,contact dermatitis, multiple sclerosis, Sjogren's syndrome and organtransplant rejection, in a mammal in need thereof, which comprisesadministering to a mammal in need thereof, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundrepresented by Formula I or a pharmaceutically acceptable salt thereof:

wherein:

represents a single bond

or a double bond

represents a single bond

or a double bond

or a triple bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl, or H; R² is H, halogen,—OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl, CN, C(O)R⁸,NR⁹R¹⁰ or hydroxyl; R³ is H, halogen, substituted or unsubstituted C₁₋₃alkyl, C(O)R⁸ or hydroxyl; R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂, C₁₋₆alkyl, —S(O)₂H, —P(O)MeOH, —P(O)(H)OH or OR¹¹; R⁵ is H, halogen, —OC₁₋₃alkyl, substituted or unsubstituted C₁₋₃ alkyl, CN, C(O)R⁸, NR⁹R¹⁰ orhydroxyl; R⁶ is H, halogen, —OC₁₋₃ alkyl, substituted or unsubstitutedC₁₋₃ alkyl, CN, C(O)R⁸, NR⁹R¹⁰ or hydroxyl; R⁷ is H, halogen, —OC₁₋₃alkyl, substituted or unsubstituted C₁₋₃ alkyl, CN, C(O)R⁸, NR⁹R¹⁰ orhydroxyl; R⁸ is H, OR¹¹ or substituted or unsubstituted C₁₋₃ alkyl; R⁹is H or substituted or unsubstituted C₁₋₃ alkyl; R¹⁰ is H or substitutedor unsubstituted C₁₋₃ alkyl; R¹¹ is H or substituted or unsubstitutedC₁₋₃ alkyl; L¹ is O, S, NH or CH₂; L² is O, S, NH or CH₂; a is 0 or 1; bis 0, 1, 2 or 3; c is 1, 2, 3 or 4; d is 1, 2 or 3; with the provisoswhen a is 1 then

represents

and when a is 0 then R¹ is O, S, NH, or CH₂.
 2. The method according toclaim 1, wherein:

represents a double bond

represents a single bond

or a triple bond

A is substituted or unsubstituted C₆₋₁₀ aryl or H; R² is H orsubstituted or unsubstituted C₁₋₃ alkyl; R³ is H; R⁴ is PO₃H₂, OPO₃H₂ orOR¹¹; R⁵ is H; R⁶ is H; R⁷ is H; R¹¹ is H or substituted orunsubstituted C₁₋₃ alkyl; L¹ is CH₂; L² is CH₂; a is 1; b is 1; c is 1,2, 3 or 4; d is 1, 2 or 3; and

represents


3. The method according to claim 1, wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl or H; R² is H; R³ is H; R⁴ isOPO₃H₂, OPO₃H₂, or OR¹¹; R⁵ is H; R⁶ is H; R⁷ is H; R¹¹ is H; L¹ is CH₂;L² is CH₂; a is 1; b is 1; c is 1, 2, 3 or 4; d is 1, 2 or 3; and

represents


4. The method according to claim 1, wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl or H; R² is H or substituted orunsubstituted C₁₋₃ alkyl; R³ is H; R⁴ is OPO₃H₂; R⁵ is H; R⁶ is H; R⁷ isH; L¹ is CH₂; L² is CH₂; a is 1; b is 1; c is 1, 2 or 4; d is 1, 2 or 3;and

represents


5. The method according to claim 1, wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl; R² is H or substituted orunsubstituted C₁₋₃ alkyl; R³ is H; R⁴ is OPO₃H₂; R⁵ is H; R⁶ is H; R⁷ isH; L¹ is CH₂; L² is CH₂; a is 1; b is 1; c is 1 or 2; d is 1, 2 or 3;and

represents


6. The method according to claim 1, wherein:

represents a double bond

represents a triple bond

A is substituted or unsubstituted phenyl; R² is H; R³ is H; R⁴ isOPO₃H₂, OPO₃H₂, or OR¹¹; R⁵ is H; R⁶ is H; R⁷ is H; R¹¹ is H; L¹ is CH₂;L² is CH₂; a is 1; b is 1; c is 2 or 3; d is 2 or 3; and

represents


7. The method according to claim 1, wherein:

represents a single bond

represents a triple bond

A is substituted phenyl; R² is H; R³ is H; R⁴ is, PO₃H₂; R⁵ is H; R⁶ isH; R⁷ is H; L¹ is CH₂; L² is CH₂; a is 1; b is 1; c is 2; d is 1; and

represents


8. The method according to claim 1, wherein the compound is selectedfrom: (3-{[(5-decylquinolin-8-yl)methyl]amino}propyl)phosphonic acid;(3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl]amino}propyl)phosphonic acid;[3-({[5-(7-phenylhept-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid;[3-({[5-(6-phenylhex-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid;[3-({[5-(7-phenylheptyl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid; (3-{[(5-dec-1-yn-1-ylquinolin-8-yl)methyl]amino}butyl)phosphonicacid;[3-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid;[3-({[5-(5-phenylpent-1-yn-1-yl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid;[3-({[5-(5-phenylpentyl)quinolin-8-yl]methyl}amino)propyl]phosphonicacid; 2-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethanol;2-({[5-(6-phenylhexyl)quinolin-8-yl]methyl}amino)ethyl dihydrogenphosphate;{3-[({5-[6-(3-methoxyphenyl)hex-1-yn-1-yl]quinolin-8-yl}methyl)amino]propyl}phosphonicacid;{3-[({5-[6-(3-methoxyphenyl)hexyl]quinolin-8-yl}methyl)amino]propyl}phosphonicacid;{3-[({5-[6-(3-methoxyphenyl)hexyl]-5,6,7,8-tetrahydroquinolin-8-yl}methyl)amino]propyl}phosphonicacid;{3-[({4-[(1E)dec-1-en-1-yl]-1-naphthyl}methyl)amino]propyl}phosphonicacid;[3-({[4-(6-phenylhex-1-yn-1-yl)-1-naphthyl]methyl}amino)propyl]phosphonicacid; 2-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)ethanol;2-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)ethyl dihydrogenphosphate;[3-({[4-(6-phenylhexyl)-1-naphthyl]methyl}amino)propyl]phosphonic acid;{3-[({4-[6-(3-methoxyphenyl)hex-1-yn-1-yl]-1-naphthyl}methyl)amino]propyl}phosphonicacid;2-[({4-[6-(3-methoxyphenyl)hex-1-yn-1-yl]-1-naphthyl}methyl)amino]ethyldihydrogen phosphate;{3-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]propyl}phosphonicacid; 2-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]ethanol;and 2-[({4-[6-(3-methoxyphenyl)hexyl]-1-naphthyl}methyl)amino]ethyldihydrogen phosphate.